Cadmium is a known environmental and industrial pollutant and a contaminant of cigarette smoke. Prior inhalation to Cd results in pulmonary adaptation which helps protect the lung against an acute inhaled dose. Metallothionein (MT), a metal and sulfur rich protein, is synthesized by the lung in response to Cd inhalation. Type II alveolar cells appear to be a primary site for MT synthesis. The role of MT and type II alveolar cells in pulmonary adaptation/tolerance to Cd will be investigated. The dose and time dependent nature of Cd adaptation/tolerance will be determined and correlated with pulmonary MT levels. Ultrastructural morphometry and quantitative autoradiography will assess type II cell hyperplasia and/or hypertrophy during Cd adaptation. Calculations of the type II cell contribution to total lung MT will be made using morphometric data and biochemical analyses of MT content of lung homogenates and isolated type II cells. Sub-cellular localization of MT in isolated type II cells and in situ in lung will be performed using immunohistochemical techniques to establish whether translocation of MT from the cytoplasm to the nucleus occurs during the Cd adaptive process. The role of glucocorticosteroids in the pulmonary response to Cd will be investigated by: (a) correlating plasma corticosterone levels during repeated or acute Cd exposures with the inflammatory cell response; (b) testing whether adrenalectomy exacerbates the toxic effects of Cd and/or reduces the ability of the lung to adapt to Cd; and (c) determining whether dexamethasone administration induces MT synthesis in the lung and/or reduces Cd-induced lung injury. The hypothesis that MT acts as a scavenger of free radicals in the lung will be tested by determining whether Cd-adapted animals, which have elevated levels of pulmonary MT, are more resistant to lung injury induced by oxygen or bleomycin. Animals made tolerant to oxygen will be tested for induction of pulmonary MT and cross tolerance to Cd. Experiments will be performed to differentiate the protective effect of metallothionein in Cd-adapted animals from that provided by glutathione, glutathione shuttle enzymes, and/or superoxide dismutase. The results of the proposed research will increase our understanding of the effects of cadmium inhalation and the roles that metallothionein and the type II cell play in pulmonary defense.